PMID- 28062921 OWN - NLM STAT- MEDLINE DCOM- 20170915 LR - 20211204 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 60 IP - 4 DP - 2017 Apr TI - Targeted deletion of Traf2 allows immunosuppression-free islet allograft survival in mice. PG - 679-689 LID - 10.1007/s00125-016-4198-7 [doi] AB - AIMS/HYPOTHESIS: Administration of anti-CD40 ligand (CD40L) antibodies has been reported to allow long-term islet allograft survival in non-human primates without the need for exogenous immunosuppression. However, the use of anti-CD40L antibodies was associated with thromboembolic complications. Targeting downstream intracellular components shared between CD40 and other TNF family co-stimulatory molecules could bypass these complications. TNF receptor associated factor 2 (TRAF2) integrates multiple TNF receptor family signalling pathways that are critical for T cell activation and may be a central node of alloimmune responses. METHODS: T cell-specific Traf2-deficient mice (Traf2TKO) were generated to define the role of TRAF2 in CD4(+) T cell effector responses that mediate islet allograft rejection in vivo. In vitro allograft responses were tested using mixed lymphocyte reactions and analysis of IFN-gamma and granzyme B effector molecule expression. T cell function was assessed using anti-CD3/CD28-mediated proliferation and T cell polarisation studies. RESULTS: Traf2TKO mice exhibited permanent survival of full MHC-mismatched pancreatic islet allografts without exogenous immunosuppression. Traf2TKO CD4(+) T cells exhibited reduced proliferation, activation and acquisition of effector function following T cell receptor stimulation; however, both Traf2TKO CD4(+) and CD8(+) T cells exhibited impaired alloantigen-mediated proliferation and acquisition of effector function. In polarisation studies, Traf2TKO CD4(+) T cells preferentially converted to a T helper (Th)2 phenotype, but exhibited impaired Th17 differentiation. Without TRAF2, thymocytes exhibited dysregulated TNF-mediated induction of c-Jun N-terminal kinase (JNK) and canonical NFkappaB pathways. Critically, targeting TRAF2 in T cells did not impair the acute phase of CD8-dependent viral immunity. These data highlight a specific requirement for a TRAF2-NFkappaB and TRAF2-JNK signalling cascade in T cell activation and effector function in rejecting islet allografts. CONCLUSION/INTERPRETATION: Targeting TRAF2 may be useful as a therapeutic approach for immunosuppression-free islet allograft survival that avoids the thromboembolic complications associated with the use of anti-CD40L antibodies. FAU - Villanueva, Jeanette E AU - Villanueva JE AD - Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. AD - Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia. FAU - Walters, Stacey N AU - Walters SN AD - Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. FAU - Saito, Mitsuru AU - Saito M AD - Centre for Kidney Research, Children's Hospital at Westmead, University of Sydney, Westmead, NSW, Australia. FAU - Malle, Elisabeth K AU - Malle EK AD - Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. FAU - Zammit, Nathan W AU - Zammit NW AD - Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. FAU - Watson, Katherine A AU - Watson KA AD - Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia. AD - Immunology Division, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC, Australia. FAU - Brink, Robert AU - Brink R AD - B Cell Biology Group, Immunology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. FAU - La Gruta, Nicole L AU - La Gruta NL AD - Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia. AD - Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. FAU - Alexander, Stephen I AU - Alexander SI AD - Centre for Kidney Research, Children's Hospital at Westmead, University of Sydney, Westmead, NSW, Australia. FAU - Grey, Shane T AU - Grey ST AD - Transplantation Immunology Group, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia. s.grey@garvan.org.au. LA - eng PT - Journal Article DEP - 20170106 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (TNF Receptor-Associated Factor 2) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) SB - IM MH - Animals MH - Blotting, Western MH - CD4-Positive T-Lymphocytes/metabolism MH - CD8-Positive T-Lymphocytes/metabolism MH - Cell Proliferation/genetics/physiology MH - Female MH - Flow Cytometry MH - *Immunosuppression Therapy MH - Islets of Langerhans Transplantation/*immunology MH - JNK Mitogen-Activated Protein Kinases/metabolism MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mice, Knockout MH - TNF Receptor-Associated Factor 2/genetics/*metabolism MH - Transplantation, Homologous OTO - NOTNLM OT - Allograft OT - Effector function OT - Immunosuppression OT - Islet OT - T cell OT - TRAF2 EDAT- 2017/01/08 06:00 MHDA- 2017/09/16 06:00 CRDT- 2017/01/08 06:00 PHST- 2016/07/27 00:00 [received] PHST- 2016/12/05 00:00 [accepted] PHST- 2017/01/08 06:00 [pubmed] PHST- 2017/09/16 06:00 [medline] PHST- 2017/01/08 06:00 [entrez] AID - 10.1007/s00125-016-4198-7 [pii] AID - 10.1007/s00125-016-4198-7 [doi] PST - ppublish SO - Diabetologia. 2017 Apr;60(4):679-689. doi: 10.1007/s00125-016-4198-7. Epub 2017 Jan 6.